Jeannette Tenthorey

Life Sciences; Agriculture and Veterinary Sciences

Cellular and Molecular Pharmacology
UCSF

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Canary in the Coal Mine: Viral Antagonists Reveal Antiviral Functions

The innate immune system relies on a small set of antiviral proteins that must act broadly to restrict a vast array of viruses. However, the true breadth of these host defenses is obscured by the fact that viruses frequently encode antagonists that neutralize antiviral proteins, masking their activity (1, 2). Current methods to unmask these hidden functions rely on species-mismatched infections, in which viruses infect host cells to which they are poorly adapted (3). However, these methods are both laborious and limited to the cell types and viral lineages for which we have experimental models. Here, I propose a new discovery paradigm that inverts the problem, discovering new antiviral activities through the signatures of viral antagonism rather than through direct infection assays. The logic is simple: if a virus encodes a dedicated antagonist, that host defense may act against the virus in question. As a proof of concept, the discovery that a poxviral protein degrades the anti-retroviral factor TRIM5 led to the unexpected finding that TRIM5 restricts this entirely distinct class of viruses (4). Building on this insight, we will systematically identify viral antagonists of innate immune factors in high throughput. We will leverage advances in large-scale DNA synthesis and ribosome profiling to mine complete viral proteomes, including previously unannotated open reading frames, for antagonists of host defenses. This novel, hypothesis-generating framework promises to reveal new antiviral activities, uncover hidden dimensions of host/virus conflict, and expand our understanding of how innate immunity defends against the vast diversity of viral threats.